5-(4-(2-(n-methyl-n-(2-pyridyl)amido)ethoxy)benzyl)thiazolidine-2, 4-dione and pharmaceutical compositions comprising the same

ABSTRACT

A compound, 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (‘Compound (I)’), or a pharmaceutically acceptable form thereof, in particulate form wherein the median value of the volume mean diameter of the particles is within the range 500 nm to 5 micrometres and medicinal uses thereof.

This invention relates to novel particulate forms of certain compounds,compositions comprising such compounds and the use of such novelpartculate forms and compositions in therapy.

The dry milling of pharmaceutically active compounds to obtain aparticle size appropriate for tablet and other formulations is wellknown in the art. In particular, air jet milling and fluid energymilling (micronising) are favoured because of the reduced risk ofcontamination.

Wet milling processes have also been disclosed for the preparation offinely divided particles of drug substance to enhance bioavailability.For example, U.S. Pat. No. 4,540,602 (Freund Industry Company Limited)discloses a process for the preparation of finely divided particles of asparingly soluble drug substance by dispersal of the drug substance inwater in the presence of a substance of high molecular weight and thenremoving the water from the disperse system. European Patent 0 499 299(NanoSystems L.L.C) discloses a wet milling procedure for the productionof particles of a crystalline drug substance, which particles have asurface modifier adsorbed on the surface in an amount sufficient tomaintain an effective average particle size (95 to 99% below) of lessthan about 400 nm. International Patent Application Publication NumberWO 99/30687 (SmithKline Beecham PLC) discloses pharmaceuticalcompositions of bicyclic drug substances, which compositions have aparticle size distribution wherein the median value of the volume meandiameter is within the range 350 to 700 nm. WO 01/13889 (SmithKlineBeecham PLC) discloses pharmaceutical compositions of nabumetone, whichcompositions have a particle size distribution of nabumetone such thatthe median particle size is in the range of about 10 micrometres toabout 0.55 micrometres. WO 00/18374 (Elan Pharma International Ltd.)discloses controlled release compositions containing a poorly-solubleagent such as a drug.

European Patent 0 306 228 (Beecham Group PLC) relates to certainthiazolidinedione derivatives disclosed as having hypoglycaemic andhypolipidaemic activity. One particular thiazolidinedione disclosed inEP 0 306 228 is5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione(hereinafter referred to as ‘Compound (I)’). European Patent 0 658 161(SmithKline Beecham PLC) discloses certain salts of Compound (I),including the maleate salt at Example 1 thereof.

It is considered that Compound (I) and pharmaceutically acceptable formsthereof have enhanced bioavailability in certain compositions ofcontrolled particle size.

It is also considered that certain compositions of therapeutic agentsand pharmaceutically acceptable forms thereof of controlled particlesize are particularly advantageous for the preparation of controlledrelease compositions. Such compositions are particularly useful for;selecting the site of delivery of the therapeutic agent in the human oranimal body, for example to avoid adverse physiological responses suchas stomach irritation; and for controlling the release of thetherapeutic agent to select the desired pharmacokinetic profile, forexample to optimise the therapeutic effect.

Accordingly, in a first aspect, the present invention provides Compound(I), or a pharmaceutically acceptable form thereof, in particulate formwherein the median value of the volume mean diameter of the particles isin the range of from 500 nm to 5 micrometres, typically less than 1micrometre.

Thus, suitable particle sizes are those wherein the median value of thevolume mean diameter of the particles is within the range of 500 nm to 5micrometres;

Suitable particle sizes also include those wherein the median value ofthe volume mean diameter of the particles is within the range of from600 nm to 5 micrometres, 700 nm to 5 micrometres, 800 nm to 5micrometres, 900 nm to 5 micrometres or 1000 nm to 5 micrometres.

Suitable particles further include those having a median value of thevolume mean diameter of the particles in the range of from: 500 nm to4.5 micrometres, 500 nm to 4.0 micrometres micrometres, 500 nm to 3.5micrometres, 500 nm to 3.0 micrometres, 500 nm to 2.5 micrometres, 500nm to 2.0 micrometres, 500 nm to 1.5 micrometres or 500 nm to 1.0micrometre. One such particle size is 500 nm to 4.5 micrometres. Onesuch particle size is 500 nm to 4.0 micrometres micrometres,. One suchparticle size is 500 nm to 3.5 micrometres. One such particle size is500 nm to 3.0 micrometres. One such particle size is 500 nm to 2.5micrometres. One such particle size is 500 nm to 2.0 micrometres. Onesuch particle size is 500 nm to 1.5 micrometres. One such particle sizeis 500nm to 1.0 micrometre.

A preferred particle size is that wherein the median value of the volumemean diameter of the particles is in the range of from 500 nm to 1000nm.

Particle sizes are measured using conventional particle size measuringtechniques, such as light scattering techniques.

The particulate form of Compound (I), or a pharmaceutically acceptableform thereof, is most suitably prepared by wet milling as an aqueousdispersion. The wet milling is preferably carried out using a suitablemilling medium in one, two or a plurality of bead mill chambers with asingle pass sequentially through the chambers. To reduce contaminationfrom mill materials, the milling medium is preferably ceramic beads ofrare earth oxides and is carried out in chambers lined with orconstructed from an abrasion-resistant polymer material such aspolyamide (e.g. Nylon). If a bead mill of more than one chamber is used,then each chamber may contain beads of a smaller diameter than those inthe previous chamber. For example, if a two chamber mill is used, thenthe beads in the first chamber are suitably of 1.25 mm diameter, and thebeads in the second chamber are of 0.4 mm diameter. The milling mediumis suitably beads made of zirconia, preferably yttria-stabilizedzirconia powder.

To assist in further processing, that is the preparation ofpharmaceutical formulations for therapeutic use, such as tablets, andinjectable dispersions, the wet milling preferably takes place in anaqueous medium, where necessary including one or more excipients such asa soluble carrier suitable for spray drying, a surfactant and/or astabiliser to maintain the particles in suspension, and ananti-agglomeration agent effective after administration of thepharmaceutical formulation to a patient.

In the aqueous medium to be subjected to the milling, Compound (I), or apharmaceutically acceptable form thereof, may be present from about 5 toabout 50% w/w. At 30% w/w and above there may be difficulties inmaintaining a suspension of the Compound (I), or a pharmaceuticallyacceptable form thereof, during milling, hence suspending and/orstabiliser may be required.

A suitable surfactant is sodium lauryl sulphate.

Suitably, the surfactant or stabiliser is present in the range fromabout 0.1 to about 0.5% w/w of the aqueous medium.

Preferably the surfactant or stabiliser is present at about 1% by weightof the compound to be processed.

Suitable anti-agglomeration agents are cellulosic thickening agents suchas hydroxypropyl methyl cellulose and hydroxyethyl cellulose.

Suitably, the anti-agglomeration agent is present in the range fromabout 1% w/w to about 2% w/w of the aqueous medium.

Preferably, the anti-agglomeration agent is present at about 1.5% w/w ofthe aqueous medium.

A suitable combined anti-agglomeration agent and suspending agent ispolyvinylpyrrolidone.

Suitably, the combined anti-agglomeration agent and suspending agent ispresent at in the range from about 0.5% w/w to about 10% w/w of theaqueous medium.

Preferably, the anti-agglomeration agent and suspending agent is presentat about 1.5% w/w of the aqueous medium.

Suitable pharmaceutically acceptable forms of Compound (I) include thosedescribed in EP 0 306 228 and EP 0 658 161, especially pharmaceuticallyacceptable salts or pharmaceutically acceptable solvates.

The suspension is buffered, suitably to a pH of 6.5, to reduce thesolubility of Compound (I), or a pharmaceutically acceptable formthereof, during the milling process.

A preferred pharmaceutically acceptable salt of Compound (I) is themaleate salt.

A preferred pharmaceutically acceptable solvate of Compound (I) is ahydrate.

The free base of Compound (I) is particularly suitable for the processof the invention due to its reduced aqueous solubility in comparison tothe salts and solvates.

As previously discussed herein, the wet milled Compound (I), or apharmaceutically acceptable form thereof, may be used in the preparationof pharmaceutical compositions.

Accordingly, in a further aspect, there is provided a composition,suitably a pharmaceutically acceptable composition, comprising aCompound (I), or a pharmaceutically acceptable form thereof, inparticulate form, wherein the median value of the volume mean diameterof the particles is in the range of from 500 nm to 5 micrometres,typically less than 1 micrometre.

Suitable particle sizes are as mentioned above. One preferred particlesize is less than 1 micrometre.

The aqueous dispersion obtained from the milling process may be useddirectly as a therapeutic agent if prepared under conditions ofappropriate hygiene. Using water and other components which meet Ph Eurstandards. However, for the preparation of formulations for use in humantherapy, it is a preferred method that the aqueous dispersion isconverted to a dried powder. This is carried out most suitably by spraydrying, typically collecting the product from the dryer using a cycloneseparator.

Additional excipients may be added to the milled aqueous suspension toproduce a suspension suitable for the spray drying process. Examples ofsuch additional excipients include carriers such as mannitol, sorbitol,lactose, lactitol, xylitol, and starch. A powder composition containingthe particulate Compound (I), or a salt thereof, is obtainable as acomposition which has good flowability and is suitable for incorporationinto a tablet formulation or a powder formulation for capsules.

A composition of this invention may be in the form of an aqueousdispersion of the particles of Compound (I), or a pharmaceuticallyacceptable form thereof, typically the product of a wet millingoperation. A composition of this invention may also be a powdercomprising particles of a Compound (I), or a pharmaceutically acceptableform thereof, typically the product of a spray drying or spraygranulation procedure suitably prepared from the particles mentionedabove.

As previously discussed herein, certain compositions of therapeuticagents and pharmaceutically acceptable forms thereof of controlledparticle size are particularly advantageous for the preparation ofcontrolled release compositions.

Accordingly, in a further aspect, the invention provides a controlledrelease pharmaceutical composition, wherein the therapeutic agent or apharmaceutically acceptable form thereof of controlled particle size anda pharmaceutically acceptable carrier are combined, wherein the carrieris selected to provide a controlled release of the therapeutic agent, ora pharmaceutically acceptable form thereof.

In another aspect the invention provides a controlled releasepharmaceutical composition, comprising a therapeutic agent and acarrier, the therapeutic agent having a controlled particle size andwherein the carrier is selected to provide a controlled release of thetherapeutic agent.

The content of the therapeutic agent in the spray dried product istypically in the range of 2 to 90% w/w.

Suitably, the therapeutic agent is Compound (I), or a pharmaceuticallyacceptable form thereof.

The milled suspension is mixed with polymers, plasticisers and glidantswhere appropriate and spray dried to produce a multiparticulatecontrolled release product. The controlled release product may suitablybe filled into capsules or compressed into a disintegrating tabletformulation.

The controlled release dosage form is a multiparticulate dosage form,where the release rate from the dosage form, and transit through thegastrointestinal tract is independent of the presence of food and thetime of dosing.

As used herein, the term “controlled release” means a composition whichhas been designed to produce a desired pharmacokinetic profile by choiceof appropriate form of the active ingredient and/or by choice offormulation. An example of a controlled release formulation is amodified release formulation. Controlled release also includescontrolled release compositions in combination with non-controlledrelease compositions.

As used herein “controlled particle size” means particles having sizesas defined herein.

As used herein, the term “modified release” means a composition whichhas been designed to produce a desired pharmacokinetic profile by choiceof formulation. Modified release also includes modified releasecompositions in combination with non-modified release compositions.

Examples of modified release include delayed, pulsed, and sustainedrelease, either alone or in any combination.

Delayed release may conveniently be obtained by use of a gastricresistant formulation such as an enteric formulation, such as a granuleincorporating a gastric resistant polymer, for example Eudragit L100-55.Other gastric resistant polymers include methacrylates, celluloseacetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, in particular, Aquateric, Sureteric,HPMCP-HP-55S.

Sustained release means providing release of the active agent over anextended period of time, for example up to 24 hours, typically 4 to 24hours.

Sustained release is typically provided by the incorporation of adisintegrating, non-disintegrating or eroding polymer into the spraydried product.

Sustained release is suitably obtained by use of a non-disintegratingformulation, for example by incorporating Eudragit RS into the spraydried product. Alternative non disintegrating matrix formulations areprovided by incorporating methacrylates, cellulose acetates,hydroxypropyl methylcellulose phthalate, in particular Eudragit L andRL, Carbopol 971P, HPMCP-HP-55S into the formulation.

Sustained release can also be achieved by incorporating a semi-permeablepolymer into the spray dried product for example methacrylates,ethylcellulose, cellulose acetate in particular Eudragit RS, orSurelease to the formulation.

Pulsed release means providing doses of the active agent in pulses, forexample providing up to 4, for example 2, pulses of active agent per 24hours.

One form of pulsed release is a combination of non-modified release ofactive agent and delayed release.

Suitably, a controlled release composition is a modified releasecomposition.

Suitably, the modified release composition is a delayed releasecomposition.

Suitably, the modified release composition is a sustained releasecomposition.

Suitably, the modified release composition is a pulsed releasecomposition.

Suitably, the composition of the invention is a combined non-modifiedand modified release composition. One example of such a combinationprovides non-modified and sustained release of active agent, for examplenon-modified release of 2 mg of Compound (I), or a pharmaceuticallyacceptable form thereof, and sustained release of 8 mg of Compound (I)or a pharmaceutically acceptable form thereof, over a 12 hour period; ornon-modified release of 2 mg of Compound (I), or a pharmaceuticallyacceptable form thereof, and sustained release of 6 mg of Compound (I),or a pharmaceutically acceptable form thereof, over a 12 hour period; ornon-modified release of 1 mg of Compound (I), or a pharmaceuticallyacceptable form thereof, and sustained release of 7 mg of Compound (I),or a pharmaceutically acceptable form thereof, over an 18 hour period.

The administration of the therapeutic agent, or a pharmaceuticallyacceptable form thereof, in particulate form to a mammal may be by wayof oral, parenteral, buccal, sub-lingual, nasal, pulmonary, ocular,vaginal, rectal or transdermal administration. Transdermaladministration includes sprays, patches, creams, and ointments.

A suitable dosage form for the spray dried controlled release product,is a tablet or capsule. The release of the therapeutic agent, or apharmaceutically acceptable form thereof, can be further delayed by theaddition of a coat to the tablet or capsule.

In particular the milled suspension of Compound (I) or apharmaceutically acceptable form thereof is suitable for formulation fordelivery by inhalation.

For example, the milled suspension is spray dried with a suitablecarrier, for example lactose, with the particle size of the spray driedproduct being controlled to be within the range of 1 to 5 micrometres.The spray dried product may then be inhaled, using, for example, asuitable device such as a dry powder dispenser.

Alternatively, the milled suspension, without further processing, may beplaced in a suitable pressurised device, for example a metered doseaerosol device, from which the product may be inhaled.

It is also considered that the inhaled formulations of Compound (I) or apharmaceutically acceptable form thereof, are suitable for combinationwith insulin to provide a combination formulation for inhalation. Thesecombination formulations may be in the form of a spray-dried product forinhalation as a dry powder, or for inhalation as a suspension from, forexample, a metered dose inhaler.

Accordingly, there is provided a pharmaceutical composition comprisingCompound (I) or a pharmaceutically acceptable form thereof incombination with insulin.

Suitably, the formulations for delivery by inhalation contain Compound(I) as the active ingredient.

Aerosol devices may be prepared using conventional methods well-known inthe art. Formulations suitable for use in aerosol devices suitablyinclude surfactants such as lecithin.

Suitable propellants for aerosol devices include chlorofluorocarbonssuch as trichloromethane, dichlorofluoromethane, and hydrofluoroalkane.

Solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are, of course,conventional in the art.

Tablets and capsules for oral administration are usually presented in aunit dose, and contain conventional excipients such as binding agents,fillers, diluents, tabletting agents (compression aids), lubricants,disintegrants, colorants, flavourings, and wetting agents. The tabletsmay be coated according to well known methods in the art.

Examples of binding agents include acacia, alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium,dextrates, dextrin, dextrose, ethylcellulose, gelatin, liquid glucose,guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, magnesium aluminium silicate, maltodextrin, methylcellulose, polymethacrylates, polyvinylpyrrolidone, pregelatinisedstarch, sodium alginate, sorbitol, starch, syrup, tragacanth.

Examples of fillers include calcium carbonate, calcium phosphate,calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulosesodium, compressible sugar, confectioner's sugar, dextrates, dextrin,dextrose, dibasic calcium phosphate dihydrate, dibasic calciumphosphate, fructose, glyceryl palmitostearate, glycine, hydrogenatedvegetable oil-type 1, kaolin, lactose, maize starch, magnesiumcarbonate, magnesium oxide, maltodextrin, mannitol, microcrystallinecellulose, polymethacrylates, potassium chloride, powdered cellulose,pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugarspheres, talc, tribasic calcium phosphate, xylitol.

Examples of lubricants include calcium stearate, glyceryl monostearate,glyceryl palmitostearate, magnesium stearate, microcrystallinecellulose, sodium benzoate, sodium chloride, sodium lauryl sulphate,stearic acid, sodium stearyl fumarate, talc, zinc stearate.

Examples of glidants include colloidal silicon dioxide, powderedcellulose, magnesium trisilicate, silicon dioxide, talc.

Examples of disintegrants include alginic acid, carboxymethylcellulosecalcium, carboxymethylcellulose sodium, colloidal silicon dioxide,croscarmellose sodium, crospovidone, magnesium aluminium silicate,microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone,polacrilin potassium, pregelatinised starch, sodium alginate, sodiumstarch glycollate.

An example of a pharmaceutically acceptable wetting agent is sodiumlauryl sulphate.

As required the solid oral compositions may be prepared by conventionalmethods of blending, filling or tabletting. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are of courseconventional in the art. The tablets may be coated according to methodswell known in normal pharmaceutical practice.

Compositions other than solid oral compositions may contain excipientssuch as carriers, formulation bases, surfactants, emulsifiers, andpenetration enhancers, and are prepared using techniques known in theart.

Suitable carriers and formulation bases include water, liquid paraffin,white soft paraffin, mygliol, polyethylene glycol, glycerol, carbomer,hydroxypropylmethyl cellulose, and methyl cellulose.

Suitable surfactants and emulsifiers include cetostearyl alcohol andsodium lauryl sulphate.

Suitable penetration enhancers include ethanol, propylene glycol, oleicacid, decylmethyl sulphoxide, dimethyl sulphoxide, dimethyl acetamide,dimethyl formamide, 2-pyrrolidone, N-methyl-2-pyrrolidone, and azone.

Compositions may, if desired, be in the form of a pack accompanied bywritten or printed instructions for use.

A unit dose will normally contain 0.01 to 1000 mg of Compound (I) or apharmaceutically acceptable form thereof.

Suitable unit doses for 1 to 100 mg, for example an amount in the rangeof from 2 to 50 mg such as 2, 4, 8, 10, and 12 mg of the activecompound.

No adverse toxicological effects are expected for the compositions ofthe invention in the above mentioned dosage ranges.

The above mentioned publications, including published patentapplications and patents, are incorporated herein by reference as thoughfully set forth herein.

The following Examples illustrate the invention but do not limit it inany way. Examples 1 and 2 are typical examples of a suspension for wetbead milling and spray drying of the milled suspension. Examples 3-7 aresuitable formulations to produce a spray dried powder with modifiedrelease of Compound (I). Example 8 is a typical formulation for acompressed tablet produced from the spray dried material. The examplesall produce a modified release dissolution profile (either in capsule ortablet form), where there is no or reduced drug release in an acidenvironment similar to that of the stomach, compared to an immediaterelease tablet, with subsequent release over 6-8 hours in a higher pHsimilar to that of the small intestine.

A suitable bead mill is the AP0010 mill from Nylacast Ltd., Leicester,UK. Bead mills manufactured by others such as Dena Systems BK Ltd.,Barnsley, UK; Drais GmbH, Mannheim, Germany; or Netzsch GmbH, Selb,Germany could also be used for the wet milling drug substances.

A 500 g batch of an aqueous suspension containing 10% w/w of compound 1(for preparation see Example 1) was passed through a Dena DM-100 beadmill, a single chamber mill, in either a single pass or recirculationconfiguration, containing 85% by volume of yttrium stabilised 0.3 mmzirconium oxide beads (from Tosoh, Japan). The chamber pressure duringprocessing varied between 0.1 and 0.2 MPa (1 and 2 bar; 14 and 28 psi).The yield exceeded 85%. The finely milled suspension was subsequentlyspray dried with addition of other excipients as required.

The milled suspensions were spray dried using a Mobile Minor SprayDryer, manufactured by Niro Ltd, Denmark. In this apparatus, the aqueoussuspension from the mill is fed by pump into a drying chamber as anatomised spray. The dried powder passes into a cyclone separator fromwhich powdered product is removed. The spray dryer was operated inaccordance with the manufacturers instructions at the followingsettings: Machine Settings Atomiser Speed about 15,000 rpm ExhaustFan/Heater Setting II Pump Speed 20 rpm Inlet Temperature 85° C. OutletTemperature 35° C.

EXAMPLES

% w/w 1. Suspension for Wet Bead Milling Compound (I) 10Polyvinylpyrollidone 1.5 Purified Water buffered to pH 6.5 to 100Particle size as measured using conventional light scatteringtechniques, have D10 and D90 values, of 300 nm to 3 micrometersrespectively. 2. Suspension of Compound I for Spray Drying MilledSuspension of Compound I 70 (as in Example 1) Mannitol 14 Water to 1003. Suspension of Compound I + Polymer for Spray Drying Milled Suspensionof Compound I 12 (as in Example 1) Eudragit L 30D (30% dispersion) 44Triethyl Citrate 0.5 Talc 0.5 Water to 100 4. Suspension of Compound I +Polymer for Spray Drying with reduced polymer content and no talc MilledSuspension of Compound I 20 (as in Example 1) Eudragit L 30D (30%dispersion) 40 Triethyl Citrate 1.0 Water to 100 5. Suspension ofCompound I + Polymer for Spray Drying with reduced polymer content andMannitol Milled Suspension of Compound I 26 (as in Example 1) Eudragit L30D (30% dispersion) 37 Mannitol 0.5 Water to 100 6. Suspension ofCompound I + Polymer for Spray Drying with combination of polymersMilled Suspension of Compound I 17 (as in Example 1) Eudragit L 30D (30%dispersion) 32 Eudragit NE (30% dispersion) 8 Water to 100 7. Suspensionof Compound I + Polymer for Spray Drying with a different polymer MilledSuspension of Compound I 12 (as in Example 1) Sureteric 15% dispersion87 Triethyl Citrate 0.5 Talc 0.5 Water to 100 8. Disintegrating ModifiedRelease Tablet Compression of spray dried material mg/tablet SD Granules(equivalent to 8 mg pfb Compound I) 102 Microcrystalline Cellulose 165Sodium starch glycolate 30 Magnesium stearate 3

1. A compound,5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,or a pharmaceutically acceptable form thereof, in particulate formwherein the median value of the volume mean diameter of the particles iswithin the range 500 nm to 5 micrometres.
 2. A compound according toclaim 1, wherein the median value of the volume mean diameter of theparticles is less than 1 micrometre.
 3. A compound according to claim 1,wherein the median value of the volume mean diameter of the particles isin the range of from 500 nm to 1000 nm.
 4. A compound according to claim1, when prepared by wet milling, suitably as an aqueous dispersion.
 5. Acompound according to claim 1, being the maleate salt of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione.6. A compound according to claim 1, being5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione.7. A pharmaceutical composition comprising a5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,or a pharmaceutically acceptable form thereof, in particulate form, witha particle size of less than 1 micrometre.
 8. A controlled releasepharmaceutical composition, comprising5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,or a pharmaceutically acceptable form thereof and a carrier, wherein the5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,or pharmaceutically acceptable form thereof, has a controlled particlesize and wherein the carrier is selected to provide a controlled releaseof the5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,or pharmaceutically acceptable form thereof.